PROGNOSTIC FACTORS OF LIVER TRANSPLANTATION FOR ACUTE-ON-CHRONIC LIVER FAILURE

ABSTRACT BACKGROUND: Liver transplantation (LT) is the only treatment that can provide long-term survival for patients with acute-on-chronic liver failure (ACLF). Although several studies identify prognostic factors for patients in ACLF who do not undergo LT, there is scarce literature about prognostic factors after LT in this population. AIM: Evaluate outcomes of ACLF patients undergoing LT, studying prognostic factors related to 1-year and 90 days post-LT. METHODS: Patients with ACLF undergoing LT between January 2005 and April 2021 were included. Variables such as chronic liver failure consortium (CLIF-C) ACLF values and ACLF grades were compared with the outcomes. RESULTS: The ACLF survival of patients (n=25) post-LT at 90 days, 1, 3, 5 and 7 years, was 80, 76, 59.5, 54.1 and 54.1% versus 86.3, 79.4, 72.6, 66.5 and 61.2% for patients undergoing LT for other indications (n=344), (p=0.525). There was no statistical difference for mortality at 01 year and 90 days among patients with the three ACLF grades (ACLF-1 vs. ACLF-2 vs. ACLF-3) undergoing LT, as well as when compared to non-ACLF patients. CLIF-C ACLF score was not related to death outcomes. None of the other studied variables proved to be independent predictors of mortality at 90 days, 1 year, or overall. CONCLUSIONS: LT conferred long-term survival to most transplant patients. None of the studied variables proved to be a prognostic factor associated with post-LT survival outcomes for patients with ACLF. Additional studies are recommended to clarify the prognostic factors of post-LT survival in patients with ACLF.


A QUEDA DA PRESSÃO PORTAL APÓS DESVASCULARIZAÇÃO ESOFAGOGÁSTRICA E ESPLENECTOMIA INFLUENCIA A VARIAÇÃO DO CALIBRE DAS VARIZES E AS TAXAS DE RESSANGRAMENTO NA ESQUISTOSSOMOSE NO SEGUIMENTO EM LONGO PRAZO?
Does the drop in portal pressure after esophagogastric devascularization and splenectomy variation of variceal calibers and the rebleeding rates in schistosomiasis in late follow-up?
Walter de Biase SILVA-NETO 1 , Claudemiro QUIRESE 1 , Eduardo Guimarães Horneaux de MOURA 2 , Fabricio Ferreira COELHO 3 , Paulo HERMAN 3 ABSTRACT -Background: The treatment of choice for patients with schistosomiasis with previous episode of varices is bleeding esophagogastric devascularization and splenectomy (EGDS) in association with postoperative endoscopic therapy.However, studies have shown varices recurrence especially after long-term follow-up.Aim: To assess the impact on behavior of esophageal varices and bleeding recurrence after post-operative endoscopic treatment of patients submitted to EGDS.Methods: Thirty-six patients submitted to EGDS portal pressure drop, more or less than 30%, and compared with the behavior of esophageal varices and the rate of bleeding recurrence.Results late post-operative varices caliber when compared the pre-operative data was observed despite an increase in diameter during follow-up that was controlled by endoscopic therapy.Evolução do calibre das varizes no período pré e pósoperatório precoce e tardio

Central Message
Acute-on-Chronic Liver Failure (ACLF) is a syndrome defined by acute decompensation of chronic liver disease associated with organ failures.This syndrome is associated with elevated short-term mortality.Liver transplant (LT) is generally the first choice for ACLF, since it can treat the syndrome and also eliminate the liver disease.need for vasoactive drug, encephalopathy degree, ACLF grade, and organs or systems failure.Pre-LT laboratory values were measured 48 hours previous to LT. Regarding to ALBI score, the values were calculated using the following equation: (log 10 bilirubin [μmol/L] × 0.66) + (albumin [g/L] × -0.085).Based on ALBI score, patients were classified on three groups according to previously defined cutoff values, resulting in three grades: ALBI grade 1 (=-2.60),grade 2 (-2.60 to=-1.39)and grade 3 (>-1.39).ACLF diagnoses followed the criteria of CLIF-C 9 : 1. Single renal failure (serum creatinine=2 mg/dL); 2. Single liver, or coagulation, or circulatory, or respiratory failure with serum creatinine between 1.5 to 1.9 mg/dL and/or mild to moderate encephalopathy; 3. Cerebral dysfunction with serum creatinine between 1.5 to 1.9 mg/dL; 4. Two or more organ failures; The ACLF classification follows the CANONIC study criteria Aiming at identifying predictors for main (death at any time during follow-up) and secondary (death on the first 90 days post-LT) outcomes, univariate analyses using Cox proportional regression were performed.In order to identify independent risk factors associated with both primary and secondary outcomes, variables with p-value<0.1 were included in multivariate models using Cox proportional hazards regression model, being considered statistically significant if p<0.05.
Survival was analysed using Kaplan-Meier method, and survival comparison was performed using the log-rank test.For all analyses, p values <0.05 was considered as statistically significant.The analyses were performed using the SPSS 18.0 program for Windows.

INTRODUCTION
A cute-on-Chronic Liver Failure (ACLF) is a syndrome defined by acute decompensation of chronic liver disease associated with organ failures.This syndrome is associated with elevated short-term mortality [2][3][4]7 . Seeral medical societies from different continents sought to establish a definition of the syndrome, based on aspects like organ failure and disease precipitating factors 10 .Among these definitions, the one established by the Chronic Liver Failure Consortium (CLIF-C) showed better sensibility and performance on mortality prediction, becoming the definition adopted in the present study 9,15,22 .
Data shows that evolution to ACLF occurs in 24-40% of all patients hospitalized for acute decompensation of cirrhosis 12 .Generally, the syndrome triggered by a precipitating event and bacterial infection is the most frequent, followed by active alcohol intake and acute reactivation of B hepatitis 2 .For as much as 40-50% of the patients, no precipitating event is identified 2,12 .In the western world, most patients that evolve to ACLF have chronic liver disease secondarily to alcohol intake or hepatitis C vírus (HCV) 6 .
The 28-days mortality of ACLF was described as 33% by the prospective CANONIC study, ranging from 15% to 80%, depending on the digree of the disease 5 .Even in patients that recover from ACLF without a LT, the estimated mortality for the next 6 months is around 40 to 60% 11 .
LT is generally the first choice for ACLF, since it can treat the syndrome and also eliminate the liver disease.This study aims to analyse the results of LT as a treatment for patients with ACLF.The survival of ACLF patients was also compared to that of all patients who recives LT for other indications in the same period.Predictors of mortality in patients undergoing LT for ACLF were also identified and analyzed

METHODS
A retrospective cohort study, which includes all adult patients (18 years old or older), submitted to LT for ACLF at HCPA between January 1, 2005, and April 30, 2021.Liver retransplants and combined transplants were excluded (liver and kidney combined transplant, for example), as well as recipients of living donors transplants.The study was approved by the Ethics Committee of the Porto Alegre University Hospital (RS) (number 42306820.0.0000.5327).
All LTs were performed by the Piggyback technique.The immunosuppression was tacrolimus, mycophenolate, and steroids based.Basiliximab induction was provided to kidney injury recipients 13 .Abdominal ultrasonography with color Doppler was periodically performed in all cases to detect hepatic and vascular complications.Oral feeding was early started after extubation in the intensive care unit.In order to avoid heterologous blood transfusion, Cell saver ® was utilized to collect blood in all cases, and autotransfusion was admnistered whenever necessary 16 .Fresh frozen plasma, cryoprecipitate, and platelets were administered as needed under thromboelastographic guidance.
The primary outcome was death, which occurred at any time during post-LT follow-up.The secondary outcome was death during the first 90 days post-LT.The patients were followed until death or to the end of the study.
A univariate analysis by the Cox regression method for overall mortality was performed (Table 3).According to the analysis, none of the studied variables was associated with the outcome.Thus, no multivariate analysis was performed.
A multivariate analysis was performed by the Cox regression method with a 1-year mortality outcome (Table 4b).According to the analysis, no variable was associated with the outcome.
A comparison between patients that survived 1 year or more and patients that died in the first year of follow-up was performed (time in days -Table 5).For the non-parametic variables, the Mann-Whitney U test was employed; in order to compare the parametric variables, the T-test was performed.The chi-square or Fischer exact test was used for the categorical variables comparison.According to this analysis, none the studied variables was associated with the outcome.
A multivariate analysis by the Cox regression method was carried out with the 90-day mortality outcome (Table 6b).According to this analysis, none of the two studied variables were associated with the outcome.
A comparison between patients who survived 90 or more days versus patients who died within the first 90 days was performed (Table 7).For non-parametric variables, the Mann-Whitney U test was used; the T-test was performed for     the comparison of parametric variables.For the comparison of categorical variables, the chi-square test or Fisher's exact test was used.According to this analysis, none of the variables studied was associated with the outcome.

DISCUSSION
The 28-day mortality of ACLF patients may reach 80% in 28 days for non-transplanted patients 20 .It is well established that LT is the only treatment capable of providing long-term survival for most patients with ACLF 1 .Several studies have shown that short and long-term survival in LT patients who undergo LT is better than that of non-transplanted patients 2,5,21,22 .Also, based on data from UNOS, a study result found that the probability of surviving while on LT waiting list for more than 30 days for patients with ACLF-3 was less than 10% vs. 90% for patients without ACLF.Therefore, among LT listed patients, those with ACLF died nine times more than those without ACLF.
The present study analyzed 25 cirrhotic patients undergoing LT in ACLF at a single center.Survival rates of 80% at 90 days, 76% at 01 year, 59.5% at 03 years and 64.1% at 05 and 07 years were observed, results comparable to those of the medical literature series 5,11,12 .No statistical differences between the overall survival of 25 patients undergoing LT versus 344 LT patients without ACLF at the same center was found.A recent study analyzed the outcomes of 116,582 patients listed for LT in the US.This study found that survival difference after 01 year of LT between patients without ACLF versus patients with 05 or 06 organ failures (ACLF-3) was only 9% 21 .In the present study, the survival difference in transplanted patients by ACLF was about 4.7% at 01 year, 16.6% at 03 years, 15.1% at 05 years, and 9.6% at 07 years.Thus, the lack of stathistically significant difference in overall post-LT survival between ACLF and no-ACLF patients could have occurred because of the relatively small sample size of the cohort analized in this study (n=369).
In this cohort study, after the univariate and multivariate analyses of several potential mortality predictors, no variables related to overall survival or mortality at 90 days and 01 year after LT were identified.In the few studies that evaluated prognostic factors of LT for ACLF, the most important survival predictor was the ACLF grade (a higher number of organ failures was associated with worse outcomes) 1,5,21 .This difference was even more evident when this outcomes of ACLF-1 or 2 as a single group were compared to those of ACLF-3V 17,19 , given that this last group involves patients with three or more organ dysfunctions (multiple organ failures).In the present study, no statistical difference at post-LT survival LIVER TRANSPLANTATION AND ACUTE-ON-CHRONIC LIVER FAILURE.

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ABCD Arq Bras Cir Dig 2023;36:e1779   among the three grades of ACLF was found 17 .Analogous to the present study, some recent studies have not found any difference in post-LT mortality between patients with different grades of ACLF.However, they have pointed to a longer hospitalization and post-LT complications in patients with ACLF grade-3 2 .Specific scores that can predict mortality in patients with chronic liver disease were evaluated in this study, and some of those scores was specific to ACLF 18,22 .In 2014, Jalan et al. compared MELD, MELD-Na, Child-Pugh and Chronic Liver Failure Consortium (CLIF-C) ACLF scores accuracy at predicting mortality in non-transplanted patients with the ACLF syndrome 9 .Among these scores, CLIF-C ACLF showed the highest accuracy (74.4% for predicting 28-day mortality vs. 0.645% for the MELD score, 0.648% for MELD-Na score and 0.653% for Child-Pugh score).However, there are no specific scores to predict post-LT mortality in patients with ACLF.
In ACLF patients not undergoing LT, CLIF-C ACLF scores above 64 are associated with mortality outcomes so high that they are generally considered unacceptable candidates for LT by some authors, considering the procedure and the institution of intensive measures as futile in these patients 17,20 .However, CLIF-C ACLF was not a poor prognostic factor in the analyses of this series.Furthermore, in the present study, three patients who scored above 64 (with 65, 70 and 78) by the CLIF ACLF score survived the first year after LT, and one of them is alive after 12 years of transplant.All these three patients showed clinical improvement, with recovery from their organ failures before being transplanted.The exact moment to carry out the transplant, particularly for cases as those of ACLF-3 with extreme severity, is extraordinarily difficult.It is believed that clinical improvement would be required for these patients before they could be considered for LT listing.This period of clinical improvement for some patients with ACLF-3 is called "golden window".The association of the pre-LT golden window with better post-LT results was recently demonstrated by Sundaram et al. 19,20 These authors evaluated the prognostic factors of mortality at one year after LT for patients in ACLF 19,20 .These authors identified an association between regression from ACLF grade III to ACLF II or I, with a significant mortality reduction in 01 year.
As for the precipitating factor of ACLF, SBP was related to ACLF precipitation in 11 patients (44%), followed by bacterial infections from other sites, in agreement with Western literature data, which include sepsis and pneumonia after SBP 8,17     other hand, none of the patients of these series presented alcohol intake as a precipitating factor, described in the literature as a decompensation frequent cause 17 .Only 2 patients (8%) had a precipitating factor identified as a non-infectious cause (indicated as drug cause and acute biliary pancreatitis).5 patients had no identified triggering factor (20%), this number being lower than that described in literature, according to which, up to 40% of the time, the cause may not be identified 2,8 .It has also been described that the number of ACLF precipitating events is more important than the type of decompensation as a prognostic factor 17 .In the present study, 3 patients (12%) had more than one precipitating factor identified, of which 2 did not survive the first year after LT.For all patients in the study, the most common dysfunction was renal injury, present in 19 patients (76%), followed by failure of blood coagulation system and liver failure (both with 11 patients -44%).When observed in relation to ACLF grades, renal failure was also the most frequent for patients in ACLF grades 1 and 2. In the medical literature, the organ/systems most common failures affecting ACLF patients are, in order: renal (56% of patients), hepatic (44%), coagulation (28%), brain (24%), circulation (17%) and respiratory (9%) 14,23 .In ACLF-3 patients, all systems appear to be highly prevalent.
One limitation of the present study was the sample size.This increases the chances of a type II error occorring.In other words, it may be that, by increasing the number of ACLF cases, some of the variables that were not significant in the univariate analysis could become significant for post-LT death outcomes in ACLF.Another difficulty in carrying out this work was that, as this was a retrospective study arising from the medical records review, the records did not always include the term ACLF, making it difficult to identify patients with the syndrome for inclusion, probably underestimating the number of cases that occured during the study period.

CONCLUSIONS
LT promotes long-term survival for most ACLF transplanted patients, similar to what occurs to other patients for other indications.None of the analyzed variables in this study was shown to be a prognostic factor associated with post-LT survival in patients with ACLF.Aditional studies evaluating prognostic factors of larger cohorts are warranted to understand the factors related to the prognosis of ACLF patients undergoing LT for ACLF.

Figure 3 -
Figure 3 -Post-liver transplant survival for 25 consecutive patients undergoing liver transplant for the treatment of Acute-on-Chronic Liver Failure (ACLF) stratified by grade (Grades 1 and 2 as a single group vs. Grade 3) (p=0.981).

Figure 1 -
Figure 1 -Survival for 25 post-liver transplant patients in Acute-on-Chronic Liver Failure.

Figure 2 -
Figure 2 -Post-liver transplant survival for 25 consecutive Acute-on-Chronic Liver Failure patients vs. 344 liver transplant patients for other indications in the same period (p=0.525,log-rank).ACLF: Acute-on-Chronic Liver Failure

Figure 3 -
Figure 3 -Post-liver transplant survival for 25 consecutive patients undergoing liver transplant for the treatment of Acute-on-Chronic Liver Failure stratified by grade (Grades 1 and 2 as a single group vs. Grade 3) (p=0.981).

Table 1a -
Frequency of organ failure in 25 patients.

Table 2 -
Pre and post-LT survival time and hospitalization length for 25 patients.

Table 4a -
Univariate analysis of 1-year post-LT mortality associated factors (Cox regression method).

Table 3 -
Univariate analysis for mortality-associated factors in 25 patients (Cox regression method).

Table 4b -
Multivariate analysis of 1-year mortality-associated factors in 25 patients (Cox regression method).
. On the

Table 6a -
Univariate analysis for mortality-associated factors in 90 days post-LT and 90-day survival time (Cox regression method).

Table 6b -
Multivariate analysis of associated factors with 90-day post-LT mortality (Cox regression method).